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Patent 2409329 Summary

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(12) Patent Application: (11) CA 2409329
(54) English Title: NOVEL CEPHALOSPORIN COMPOUNDS AND PROCESS FOR PREPARING THE SAME
(54) French Title: NOUVEAUX COMPOSES DE CEPHALOSPORINE ET PROCEDES DE PREPARATION DE CES DERNIERS
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 501/24 (2006.01)
  • C07D 501/00 (2006.01)
(72) Inventors :
  • LEE, HYANG-SOOK (Republic of Korea)
  • KIM, GEUN-TAE (Republic of Korea)
  • JANG, YONG-JIN (Republic of Korea)
  • YOUN, HA-SIK (Republic of Korea)
  • LEE, SEONG-BAEK (Republic of Korea)
  • LEE, CHANG-SEOK (Republic of Korea)
  • OH, SEONG-HO (Republic of Korea)
  • RYU, EUN-JUNG (Republic of Korea)
(73) Owners :
  • LG LIFE SCIENCES LTD. (Republic of Korea)
(71) Applicants :
  • LG LIFE SCIENCES LTD. (Republic of Korea)
(74) Agent: ROBIC
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2001-06-14
(87) Open to Public Inspection: 2002-01-17
Examination requested: 2002-11-15
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/KR2001/001026
(87) International Publication Number: WO2002/004463
(85) National Entry: 2002-11-15

(30) Application Priority Data:
Application No. Country/Territory Date
2000/38817 Republic of Korea 2000-07-07

Abstracts

English Abstract




The present invention relates to a novel cephalosporin compound and
pharmaceutically acceptable non-toxic salt, physiologically hydrolysable
ester, hydrate, solvate or isomer thereof, to a pharmaceutical composition
containing the compound and to a process for preparing the compound.


French Abstract

La présente invention concerne un nouveau composé de céphalosporine et un sel non toxique, un ester physiologiquement hydrolysable, un hydrate, un solvate ou un isomère pharmaceutiquement acceptable de ce dernier ; une composition pharmaceutique contenant le composé et un procédé de préparation dudit composé.

Claims

Note: Claims are shown in the official language in which they were submitted.



27

CLAIMS

1. A cephalosporin compound represented by the following formula (I):
Image
and pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable
ester, hydrate,
solvate or isomer thereof, in which
R1 and R2 independently of one another represent hydrogen, halogen, C1-6
alkyl, C1-6
alkylthio, aryl, arylthio, or C5-6 heteroaryl containing one or two hetero
atoms
selected from the group consisting of nitrogen atom and oxygen atom;
R3 represents hydrogen or a carboxy-protecting group;
Q represents O, S or CH2;
Z represents CH or N;
n denotes an integer of 0 or 1;
Ar represents a heteroaryl group represented by one of the following formulas:


28

Image
wherein X, Y, W, A, B, D, E, G and I independently of one another represent N
or C (or
CH), provided that the six-membered ring forms a pyrimidine structure;
R4 represents hydrogen or C1-4 alkyl, or amino substituted or unsubstituted
with a
substituent selected from the group consisting of C1-6 alkyl and C1-6
hydroxyalkyl;
R5 and R6 independently of one another represent hydrogen, hydroxy, C1-4 alkyl
or C1-6
alkylthio, or amino substituted or unsubstituted with a substituent selected
from the
group consisting of C1-6 alkyl, C1-6 hydroxyalkyl and C1-6 aminoalkyl;
R7, R8, R9, R10 and R11 independently of one another represent hydrogen or C1-
6 alkyl, or
amino substituted or unsubstituted with a substituent selected from the group
consisting of C1-6 alkyl, C1-6 hydroxyalkyl and C1-6 aminoalkyl; and
~ denotes a single bond or a double bond.
2. The compound of claim 1, wherein the compound is selected from the group
consisting of the following:
(6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-dichlorophenyl)-
sulfanyl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic
acid,
(6R,7R)-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-dichloro-
phenyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-


29

carboxylic acid,
(6R,7R)-3-[(6-amino-2-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,6-dichloro-
phenyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic
acid,
(6R,7R)-3-[(4-amino-2-pyrimidinyl)sulfanyl]-8-oxo-7-[(phenylacetyl)amino]-5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
(6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-({ 2-[(2, 6-dichloro-4-
pyridinyl)sulfanyl]acetyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-,ene-2-
carboxylic acid, and
(6R,7R)-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,6-dichloro-4-
pyridinyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
3. A process for preparing the compound of formula (I) according to claim
1, which
comprises reacting a compound of formula (V):
Image
wherein R1, R2, R3, Z, Q and n are as defined in claim 1, L represents a
leaving group and p
is 0 or 1, with a compound of formula (VI):
HS~Ar (VI)


30

wherein Ar is as defined in claim 1, in a solvent or reducing S.fwdarw.oxide
of a compound of
formula (VII):
Image
wherein R1, R2, R3, Z, Q, n and Ar are as defined in claim 1.
4. The process of claim 3, which further comprises removing acid-protecting
group.
5. A process for preparing the compound of formula (I) according to claim 1,
which
comprises reacting the compound of formula (VI):
HS~Ar (VI)
wherein Ar is as defined in claim 1, with a compound of formula (X):
Image
wherein R3 is as defined in claim 1, p is 0 or 1, L is a leaving group and P'
represents an


31

amino-protecting group, to provide a compound of formula (XI):
Image
wherein R3, P', Ar and p are as defined above; removing the amino-protecting
group P'
from the compound of formula (XI), activating a carboxylic acid of formula
(VIII) or its
salt with an acylating agent, and then reacting the activated form of the
compound of
formula (VIII) with the deprotected compound of formula (XI) from which
protecting
group P' is removed.
6. An antibacterial composition containing the compound of formula (I) or its
pharmaceutically acceptable salt according to claim 1 as an active ingredient,
together with
a pharmaceutically acceptable carrier.

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02409329 2002-11-15
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1
NOVEL CEPHALOSPORIN COMPOUNDS AND PROCESS FOR
PREPARING THE SAME
TECHNICAL FIELD
The present invention relates to a novel cephalosporin compound useful as an
antibiotic agent. More specifically, the present invention relates to a novel
cephalosporin
compound represented by the following formula (I), which is useful as an
antibacterial
agent, and particularly, exhibits a potent activity against strains such as
methicillin-
to resistant Staphylococcus aureus (MRSA):
Ri \ n N S
(Q)
R2~ O / N / S~Ar
O
CO2R3
and pharmaceutically acceptable non-toxic salt, physiologically hydrolyzsable
ester,
hydrate, solvate or isomer thereof, in which
R' and R2 independently of one another represent hydrogen, halogen, C,_6
alkyl, C,_6
alkylthio, aryl, arylthio, or CS_6 heteroaryl containing one or two hetero
atoms
selected from the group consisting of nitrogen atom and oxygen atom;
R3 represents hydrogen or a carboxy-protecting group;
2o Q represents O, S or CHz;
Z represents CH or N;
n denotes an integer of 0 or 1;


CA 02409329 2002-11-15
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2
Ar represents a heteroaryl group represented by one of the following formulas:
R8
I
R4 R6 A~BwD~R9
E\G-Rio
\ Y~ Y _
Y
W_R~ , ~~ /W or -C~ / I~Rm
X
X X
RS RS RS
wherein X, Y, W, A, B, D, E, G and I independently of one another represent N
or C (or
CIA, provided that the six-membered ring forms a pyrimidine structure;
R4 represents hydrogen or C,~ alkyl, or amino substituted or unsubstituted
with a
substituent selected from the group consisting of Cl_6 alkyl and C,_6
hydroxyalkyl;
RS and R6 independently of one another represent hydrogen, hydroxy, C,~ alkyl
or C,_6
alkylthio, or amino substituted or unsubstituted with a substituent selected
from the
group consisting of C,_6 alkyl, C,_6 hydroxyalkyl and C,_6 aminoalkyl;
R', R8, R9, R'° and R" independently of one another represent hydrogen
or C,_6 alkyl, or
amino substituted or unsubstituted with a substituent selected from the group
consisting of C,_6 alkyl, C,_6 hydroxyalkyl and C,_6 aminoalkyl; and
denotes a single bond or a double bond.
The present invention also relates to a process for preparing the compound of
formula (I), as defined above, and to an antibacterial composition containing
the compound
of formula (I) as an active ingredient.


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3
BACKGROUND ART
Cephalosporin-based antibiotics have been widely used for treatment of
infectious diseases caused by pathogenic bacteria in human and animals. They
are
particularly useful for treatment of diseases caused by bacteria resistant to
other antibiotics
such as penicillin compounds and for treatment of penicillin-hypersensitive
patients. In
most of he cases for treating such infectious diseases, it is preferred to use
antibiotics
showing an antimicrobial activity against both of gram-positive and gram-
negative
microorganisms. It has been very well known that such antimicrobial activity
of
to cephalosporin antibiotics is largely influenced by the kind of substituents
present at 3- or 7-
position of cephem ring. Therefore, according to the attempt to develop an
antibiotic
agent showing a potent antimicrobial activity against broad strains of gram-
positive and
gram-negative microorganisms numerous cephalosporin antibiotics having various
substituents introduced into 3- or 7-position have been developed up to the
present.
For instance, British Patent No. 1,399,086 illustrates broadly and generically
cephalosporin derivatives represented by~the following formula (II):
O
A
H
N~OR~ ~ N ~ B
C02H
in which
R6 represents hydrogen or an organic group;
R~ is an etherified monovalent organic group, which is linked to oxygen via
carbon atom;


CA 02409329 2002-11-15
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4
A represents -S- or >S~O; and
B represents an organic group.
Since development of those compounds, many attempts to develop antibiotic
agents having broad antibacterial spectrum have been made and, as a result,
numerous
s cephalosporin antibiotics have been developed. According to their
development of them,
many studies to introduce acylamido group into 7-position and a certain
specific group into
C-3 position of the cephem nucleus of formula (II) have also been made in
various points
of view.
Recently, resistance strains of gram-positive microorganisms, particularly
methicillin-resistant Staphylococcus auYeus (MRSA) have been recognized as the
cause of
serious hospital infection and therefore, many attempts have been made to
introduce
arylthio group into C-3 position to develop cephalosporin compounds showing a
potent
activity against MRSA.
Thus, Japanese laid-open Pubilcation 98-36375 discloses broadly and
generically
cephalosporin derivatives represented by the following formula (III) wherein
arylthio
group is introduced into C-3 position to increase the activity against broad
pathogenic
strains:
r ~
O
WA N
H
Rio
R9
in which
R$ represents substituted allcylthio, aryl, arylthio, aryloxy or heterocyclyl
group;


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
A represents protected amino, hydroxy or methylene group;
R9 represents protected carboxy or carboxylate;
R,o represents halo, cyano, amidino, guanidino, azido, nitro, substituted
alkyl, alkenyl,
dichloroalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, acyl,
5 carbamoyl, carbamoyloxy, alkoxyimino, ureido, alkylsulfmyl, alkylsulfonyl or
sulfamoyl, or 2-substituted pyrimidinyl, quinazolinyl, purinyl, pyrazolo[3,4-
d]pyrimidinyl, pyrazolo[4,3-d]pyrimidinyl, [1,2,3]triazolo[4,5-d] pyrimidinyl
or
phtheridinyl; and
m denotes 0 or 1.
to In the above patent, various heteroaromatic rings are introduced into
thioaryl
moiety at C-3 position but are different from 4-pyrimidine or 2-pyridine ring
used in the
present invention. In other words, the above Japanese patent mentions various
substituted
or unsubstituted pyrimidinyl groups as the substituent present at C-3 position
but does not,
mention 4-pyrimidine or 2-pyridine ring as used in the present invention.
The attempt has been made to develop cephalosporin compounds, which can show
a potent activity against serious hospital infection caused by methicillin-
resistant
Staphylococcus aureus (MRSA), by introducing acyl group into position 7 and
pyridine
group' into C-3 position. Typical example thereof is the compounds of formula
(I~
disclosed in European laid-open Publication EP 96-72742:
AcyINH S RI i
N / S ~ N~ Ris
O
C02H Ri2
in which


CA 02409329 2002-11-15
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6
Acyl substituent is Ar-S-CHZ CO-, wherein Ar represents hydrophobic
substituted phenyl,
pyridyl or benzthiazolyl group;
Rm and R,2 independently of one another represent hydrogen, alkyl or
aminoalkylcarbonylamino; and
R13 represents substituted aliphatic, aromatic or arylaliphatic group or a
group containing
sugar moiety.
In the above European patent, various heteroaromatic rings are introduced into
thioaryl moiety present at C-3 position but are different from the substituent
present at C-3
position of the compound according to the present invention.
to That is, the present invention is characterized by introduction of various
substituted or unsubstituted pyrimidinyl or 2-pyridyl groups, which are not
disclosed in
any of the above patents, into C-3 position.
DISCLOSURE OF THE INVENTION
Thus, the present inventors have conducted extensive and intensive researches
to
develop cephalosporin compounds showing broad antibacterial activity against
gram-
positive microorganisms including MRSA. As a result, we have identified that a
certain
cephalosporin compound having optionally substituted pyrimidinyl group at C-3
position
2o meets with the above requirement, and then completed the present invention.
Therefore, the purpose of the present invention is to provide a compound of
formula (I), as defined above, and pharmaceutically acceptable non-toxic salt,
physiologically hydrolyzable ester, hydrate, solvate or isomer thereof.
Further, the purpose of the present invention is to provide a process for
preparing
the compound of formula (I) and an antibacterial composition containing the
compound of
formula (I) as an active ingredient.


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7
BEST MODE FOR CARRYING OUT THE INVENTION
The purpose of the present invention is to provide a novel cephalosporin
compound represented by the following formula (I):
R1
(Q)n N S
O / N / S~Ar
R O
C02R3
and pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable
ester, hydrate,
solvate or isomer thereof, in which
1o RI and R2 independently of one another represent hydrogen, halogen, C,_6
alkyl, C,_6
alkylthio, aryl, arylthio, or CS_6 heteroaryl containing one or two hetero
atoms
selected from the group consisting of nitrogen atom and oxygen atom;
R3 represents hydrogen or a carboxy-protecting group;
Q represents O, S or CH2;
Z represents CH or N;
n denotes an integer of 0 or 1;
Ar represents a heteroaryl group represented by one of the following formulas:


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
8
Rg
4 iB\ iR9
R R6 A D EyG-RIo
\ Y~ Y - I
Y
W_R~ , ~~ /W or --C~ ~ ~Rm
X
X~ X
Rs Rs Rs
wherein X, Y, W, A, B, D, E, G and I independently of one another represent N
or C (or
CH), provided that the six-membered ring forms a pyrimidine structure;
R4 represents hydrogen or C,~ alkyl, or amino substituted or unsubstituted
with a
substituent selected from the group consisting of C,_6 alkyl and C,_6
hydroxyalkyl;
RS and R6 independently of one another represent hydrogen, hydroxy, C,~ alkyl
or' C,_6
alkylthio, or amino substituted or unsubstituted with a substituent selected
from the
group consisting of C,_6 alkyl, C,_6 hydroxyalkyl and C,_6 aminoalkyl;
R', R8, R9, Rl° and R" independently of one another represent hydrogen
or C,_6 alkyl, or
to amino substituted or unsubstituted with a substituent selected from the
group
consisting of C,_6 alkyl, C,_6 hydroxyalkyl and C,_6 aminoalkyl; and
denotes a single bond or a double bond.
The compound of formula (I) according to the present invention can be
administered in the form of an injectable formulation or an oral formulation
depending on
1s the purpose of its use.
Pharmaceutically acceptable non-toxic salts of the compound of formula (I)
include salts with inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric
acid, sulfuric acid, etc., salts with organic carboxylic acids such as acetic
acid,
trifluoroacetic acid, citric acid, formic acid, malefic acid, oxalic acid,
succinic acid, benzoic
2o acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic
acid, etc., or with
methanesulfonic acid or para-toluenesulfonic acid, and salts with other acids
which have


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
been well-known and widely used in the technical field of penicillins and
cephalosporins.
These acid addition salts can be prepared according to any of the conventional
methods.
Further, the compound of formula (I) can also form a non-toxic salt with a
base. The
base which can be used for this purpose includes inorganic bases such as
alkaline metal
15 hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline
metal bicarbonates
(e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline metal
carbonates (e.g.
sodium carbonate, potassium carbonate, calcium carbonate, etc.), etc., and
organic bases
such as amino acids.
Examples of physiologically hydrolysable esters of the compound of formula (I)
to include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl,
glycyloxymethyl,
phenylglycyloxymethyl, 5-methyl-2-oxo-1,3-dioxolen-4-yl methyl esters or other
physiologically hydrolysable esters which have been well-known and widely used
in the
field of penicillins and cephalosporins. These esters can be prepared
according to any of
the known conventional methods.
is Typical examples of the compound of formula (I) according to the present
invention include the following:
I=1: (6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-
dichlorophenyl)-
sulfanyl] acetyl ~ amino)-8-oxo-5-this-1-azabicyclo [4.2. 0] o ct-2-ene-2-
carboxyli c
acid,
2o I-2: (6R,7R)'-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-
dichloro-
phenyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-I-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid,
I-3: (6R,7R)-3-[(6-amino-2-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,6-
dichloro-
phenyl) sulfanyl] acetyl ~ amino)-8-oxo-5-thia-1-azab icyclo [4.2. 0] oct-2-
ene-2-
25 carboxylic acid,
I-4: (6R,7R)-3-[(4-amino-2-pyrimidinyl)sulfanyl]-8-oxo-7-[(phenylacetyl)amino]-
5-


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
I-5: (6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-( f 2-[(2,6-dichloro-4
pyridinyl) sulfanyl] acetyl } amino)-8-oxo-5-thia-1-azabicyclo [4.2. 0] oct-2-
ene-2
carboxylic acid, and
5 I-6: (6R,7R)-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,6-
dichloro-4-
pyri dinyl) sulfanyl] acetyl ~ amino)-8-oxo-5-thia-1-azabicyclo [4.2. 0] o ct-
2-ene-2-
carboxylic acid.
According to the present invention, the compound of formula (I):
Rl ~ (Q)n N
Z~ O ~ N / S~Ar
R O
C02R3
to
wherein R', R2, R3, Z, Q, n and Ar are as defined above, and pharmaceutically
acceptable
non-toxic salt, physiologically hydrolysable ester, hydrate, solvate or isomer
thereof can be
prepared by a process which comprises reacting a compound of formula (~:
r -i
R1 _ N
Q)
Z / O
R C
wherein R', Rz, R3, Z, Q and n are as defined in the formula (I), L represents
a leaving


CA 02409329 2002-11-15
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11
group and p is 0 or 1, with a compound of formula (VI):
HS-Ar
wherein Ar is as defined in the formula (I), in a solvent and, if necessary,
removing the
acid-protecting group before or after the reaction, or reducing S~oxide of a
compound of
formula (VII):
O
Rl N S
~ ~ (Q)~
Z / O f N / S~Ar
R O
CO2Rs
wherein Rl, R2, R3, Z, Q, n and Ar are as defined in the formula (I).
In the process for preparing the compound of formula (I) according to the
present
invention, the compound of formula (VI) is used in an amount of 1 to 2 moles
with respect
to one mole of the compound of formula (V).
In the process for preparing the compound of formula (I) by reacting the
compound of formula (V) with the compound of formula (VI) according to the
present
invention, the reaction temperature can be varied within a broad range and is
generally in
the range of -10°C to 50°C, preferably in the range of
20°C to 35°C.
The process for preparing the compound of formula (I) according to the present
invention can be carried out using a solvent. Suitable solvent for this
purpose is a non-
reactive solvent and includes, for example, dimethylformamide,
dimethylsulfoxide,
2o methylene chloride, etc., or the mixture thereof.
In the above process, carboxy-protecting group R3 is desirably the group which


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12
can be readily removed under mild condition. Typical examples of carboxy-
protecting
group R3 include (lower) alkyl ester (e.g. methyl ester, t-butyl ester, etc.),
(lower) alkenyl
ester (e.g. vinyl ester, allyl ester, etc.), (lower) alkylthio (lower) alkyl
ester (e.g.
methylthiomethyl ester, etc.), halo (lower) alkyl ester (e.g. 2,2,2-
trichloroethyl ester, etc.),
5, substituted or unsubstituted aralkyl ester (e.g. benzyl ester, p-
nitrobenzyl ester, p-
methoxybenzyl ester, etc.) or silyl ester. These carboxy-protecting groups can
be readily
removed under mild reaction conditions such as hydrolysis, reduction, etc. to
generate a
free carboxy group, and appropriately selected depending on the chemical
properties of the
compound of formula (I).
to A suitable leaving group L is, for example, methanesulfonyloxy group,
trifluoromethanesulfonyloxy group, etc. (see, Synthesis of its precursor 3-
hydroxy
compounds: Hel. Chem. Acta 1974, 57, 1919-1934).
The dotted line in the formula . (~ represents each of 2-cephem and 3-cephem
compounds, as shown in the following, or their mixture:
1 g ~ O~p
R
(Q)~N S
I I (Va)
Z / O / N / L
R O
CO2Rs
O
Rl H ~ ~ J p
(Q) ~N S
Z / O ~ IV ~ (Vb)
R~ O -L
C02R3
wherein R', R2, R3, Z, Q, n, p and L are as defined above.


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13
The compound of formula (~ can be prepared by activating a compound of
' ,formula (VIII):
r ~
R1 N
Z / O
R ~
R1
(Q) ~OH
Z IOI
R
wherein R', R2, R3, Z, Q, n, p and L are as defined above, or its salt with an
acylating agent
and then reacting the resulting activated compound with a compound of formula
(IX):
O~p
H2N S
/ N
~L
O
CO2R3
to
wherein R3, p and L are as defined above.
The dotted line in the formula (IX) represents each of 2-cephem and 3-cephem
compounds, as shown in the following, or their mixture:


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14
~ pip
HZN S
N / (IXa)
O ~L
Cp2R3
C ~~p
H2N S
~ N 1 (~)
O ~L
~p2R3
wherein R3, p and L are as defined above.
The compound of formula (I) can also prepared by reacting the compound of
formula (VI):
HS-Ar
wherein Ar is as defined above, with a compound of formula (X):
~O~~p
' P'HN S
~ N .r
O ~L
Cp2R3
.10
wherein R3, p and L are as defined above and P' represents an amino-protecting
group, to
provide a compound of formula (XI):


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
~ ~~.p
p~I~V S
f N -r Ar
~S
C~2R3
wherein R3, P', Ar and p are as defined above; removing the amino-protecting
group P'
from the compound of formula (XI), activating a carboxylic acid of formula
(VIII) or its
5 salt with an acylating agent, and then reacting the activated form of the
compound of
formula (VIII) with the deprotected compound of formula (XI) from which
protecting
group P' is .removed (see, Preparation of activated carboxylic acids and
reaction of
activated carboxylic acid with amine group: EP 94105499.1, EP 94108809.8).
In the above process for preparing the compound of formula (I), the compound
of
1o formula (~ . is used generally in an amount of 0.5 to 2 moles with respect
to one mole of
the compound of formula (VI) and the compound of formula (VIII) is used
generally in an
amount of 1 to 2 moles with respect to one mole of the compound of formula
(XI).
In reacting the compound of formula (VI) with the compound of formula (X), the
reaction temperature can be varied within a broad range and is generally in
the range of -
15 80°C to 40°C. This reaction can be carried out in a solvent.
Suitable solvent which can
be used in this reaction is an inert solvent and includes, for example,
tetrahydrofuran,
dimethylformamide, dimethylsulfoxide, methylene chloride and the mixture
thereof.
The dotted line in the formula (X) represents each of 2-cephem and 3-cephem
compounds, as shown in the following, or their mixture


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
16
~ pip
P'HN S
~)
p 'L
C02R3
~ ~~p
P'HN S
N (~)
L
O
CO2R3
wherein R3, p, L and P' are as defined above.
In preparing the compound of formula (V), an acylated derivative as the
activated
form of the compound of formula (VIII) includes acid chlorides, acid
anhydrides, mixed
acid anhydrides (preferably, acid anhydrides formed with methylchloroformate,
mesitylenesulfonyl chloride, p-toluenesulfonyl chloride or chlorophosphate) or
activated
esters (preferably, esters formed from the reaction with N-
hydroxybenzotriazole in the
to presence of a condensing agent such as dicyclohexylcarbodiimide), etc. In
addition, the
acylation reaction can also be practiced by using a free acid compound of
formula (VIII) in
the presence of a condensing agent such as dicyclohexylcarbodiimide or
carbonyldiimidazole. Further, the acylation reaction is well practiced
generally in the
presence of an organic base, preferably a tertiary amine such as
triethylamine,
dimethylaniline, pyridine, etc., or an inorganic base such as sodium
bicarbonate, sodium
carbonate, etc. The solvent which can be used in this reaction includes
halogenated
hydrocarbon such as methylene chloride, chloroform, etc., tetrahydrofuran,
acetonitrile,
dimethylformamide or dimethyl acetamide. The mixed solvent comprising two or
more
solvents selected from the above can also be used. The reaction can also be
carried out in


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
17
an aqueous solution.
The reaction temperature in the acylation reaction is in the range of -
50°C to 50°C,
preferably in the range of -30°C to 20°C. The acylating agent
for the compound of
formula (VIII) can be used in an equimolar amount or a slightly excessive
amount, i.e. in
an amount of 1.05 to 1.2 equivalent weights, with respect to an equivalent
weight of the
compound of formula (I~ or (~.
In preparing the compound of formula (I) as defined above, the amino-
protecting
' , ~ group or the acid-protecting group present in the compound of formula
(V) can be removed
by any of the conventional methods widely known in the field of
cephalosporins. That is,
to the protecting groups can be removed by hydrolysis or reduction. Acid
hydrolysis is
useful for removing tri(di)phenylmethyl group or alkoxycarbonyl group and is
carried out
using an organic acid such as formic acid, trifluoroacetic acid, p-
toluenesulfonic acid, etc.,
or an inorganic acid such as hydrochloric acid, etc.
The resulting product from the above processes can be treated with various
. , ,methods such as recrystallization, electrophoresis, silica gel column
chromatography or ion
exchange resin chromatography to separate and purify the desired compound of
formula
(I).
Another purpose of the present invention is to provide a pharmaceutical
composition containing the compound of formula. (I) or its pharmaceutically
acceptable
salt as an active ingredient, together with a pharmaceutically acceptable
carrier.
The compound according to the present invention can be administered in the
form
of an injectable formulation or an oral formulation depending on the purpose
of its use.
The compound of formula (I) of the present invention can be formulated using
known pharmaceutically acceptable carriers and excipients according to the
known method
to prepare a unit dosage form or to be introduced into a mufti-dosage
container. The
formulations can be in the form of a solution, suspension or emulsion in an
oil or aqueous


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
. , 18
medium and can contain conventional dispersing agent, suspending agent or
stabilizing
agent. In addition, the formulation can also be in the form of a ready-to-use
dry powder
which can be used by dissolving with a sterile, pyrogen-free water before its
use. The
compound of formula (I) can also be formulated in the form of a suppository by
using
conventional suppository bases such as cocoa butter or other glycerides. Solid
dosage
form for oral administration includes capsules, tablets, pills, powders and
granules, with
capsules and tablets being particularly useful. For the tablets and pills, it
is preferred to
provide an enteric coating. Solid dosage form can be prepared by mixing the
active
compound of formula (I) according to the present invention with one or more
inert diluents
1o such as sucrose, lactose, starch, etc., and carriers including lubricants
such as magnesium
stearate, disintegrating agents, binders, etc.
If necessary, the compound of the present invention can be administered in
combination with other antibacterial agent such as penicillins or other
cephalosporins.
In formulating the compound of formula (I) according to the present invention
into
i5 the unit dosage form, it is preferred that the unit dosage form contains
the active ingredient
of formula (I) in an amount of about 50 to 1,500 mg. The dosage of the
compound of
formula (I) is suitably selected under the physician's prescription depending
on various
factors including weight and age of patient, particular conditions and
severity of diseases to
be treated, etc. However, the daily dosage for treatment of adult man
generally
20 corresponds to about 500 to 5,000 mg of the compound of formula (I)
depending on the
frequency and intensity of administration. For intramuscular or intravenous
injection to
adult man, a total daily dosage in the range of about 150 to 3,000 mg is
generally sufficient.
However, in case of infections caused by some pathogenic strains, it may be
preferred to
more increase the daily doage.
25 The compound of formula (I) and its non-toxic salt, preferably salts with
alkali
metals, alkaline earth metals, inorganic acids, organic acids and amino acids,
according to
the present invention exhibit a potent antimicrobial activity and a broad
antibacterial


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
19
spectrum against broad pathogenic microorganisms including various gram-
positive strains
and therefore, are very useful for prevention and treatment of diseases caused
by bacterial
infection in animals including human being.
The present invention will be more specifically illustrated by the following
preparations and examples. However, it should be understood that these
preparations and
examples are provided only to help clear understanding of the present
invention but do not
intend to limit the present invention in any manner.
EXAMPLES
to
Preparation 1
Synthesis of benzhydryl 7-amino-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-8-oxo-
5-
thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate
. 2 g (4.025 mmol) of (6R,7R)-benzhydryl 7-amino-3-[(methoxysulfanyl)oxy]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride was
dissolved in
4/10 ml of tetrahydrofuran/dimethylformamide, and the temperature of the
reaction vessel
was then lowered to -78°C. 0.731 mg (3.823 mmol) of 2,4-diamino-6-
mercapto
pyrimidine 1/2 sufate was added to the reaction solution. The reaction mixture
was
2o stirred for 24 hours while gradually increasing the reaction temperature to
room
temperature. Excessive ether was added to solidify the resulting product,
which was
filtered and then dried under nitrogen to obtain 2.23 g (yield 85%) of the
title compound.
'H-NMR (CD30D) 8 7.36-7.30 (10H, m), 7.01 (1H, s), 5.91 (1H, s), 5.54-5.52
(1H,
d, J=5.5Hz), 5.28-5.27 (1H, d, J=5.5Hz), 4.05-4.01 (1H, Abq, J=17.9Hz), 3.70-
3.67 (1H,
Abq, J=18,3Hz).


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
Mass (m/e) 376
Example 1
Synthesis of (6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-
dichloro-
~5 phenyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic
acid
2.23 g of benzhydryl 7-amino-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-8-oxo- 5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was treated with
trifluoroacetic acid and
to anisole to obtain 1.8 g of deprotected trifluoroacetate compound. 0.5 g
(1.1012 mmol) of
the resulting salt compound was dissolved in 5 ml of dichloromethane and then
cooled to
0°C. 1.1 ml of N,O-bistrimethylsilyl acetamide (BSA) was added and the
mixture was
stirred at 0°C for 10 minutes. To the reaction mixture were added 0.31
g (1.12113 mmol)
of 2,5-dichlorophenylthioacetyl chloride and 0.045 ml (0.5506 mmol) of
pyridine. The
15 temperature of the reaction vessel was increased to 10°C and stirred
for 2 hours. The
reaction was stopped with water and ammonium chloride. The resulting product
was
solidified with diethyl ether to obtain 0.28 g of the solid product, which was
then purified
with a high pressure fractional liquid chromatography to obtain 0.080 g (yield
14.5%) of
the title compound.
'H-NMR (DMSO-d6) 8 9.34 (1H, d, J=7.8Hz), 7.48-7.46 (2H, m), 7.26-7.24 (1H,
m), 6.65 (1H, br, s), 6.34 (1H, br, s), 5.76-5.67 (2H, m, s), 5.19-5.18 (1H,
d, J=4.55Hz),
3.98 (2H, s).
Mass (m/e) 558


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
21
Example 2
Synthesis of (6R,7R)-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-

dichlorophenyl)sulfanyl] acetyl)amino)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-
ene-2-
carboxylic acid
' .,
0.085 g (yield 33.3%) of the title compound was obtained according to the same
procedure as Example 1.
'H-NMR (CD30D) 8 8.89 (1H, m), 7.46 (1H, s), 7.37-7.35 (1H, d, J=8.25Hz),
to 7.16 (1H, m), 5.78-5.77 (2H, s, d), 5.25-5.24 (1H, d, J=SHz), 3.88 (1H,
Abq, J=17.9Hz),
3.82 (2H,, s), 3.51 (1H, Abq, J=17.9Hz).
Mass (m/e) 559
Example 3
Synthesis of (6R,7R)-3-[(6-amino-2-hydroxy-4-pyrimidinyl)sulfanyl]-7-({2-[(2,5-

dichlorophenyl)sulfanyl]acetyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene-2-
carboxylic acid
0.07 g (yield 30.0%) of the title compound was obtained according to the same
procedure as Example 1.
'H-NMR (CD30D) 8 8.91-8.89 (1H, m), 7.45 (1H, s), 7.37-7.35 (1H, d, J=8.25Hz),
7.19 (1H, m), 5.93 (1H, s), 5.72-5.71 (1H, d, J=5Hz), 5.29-5.27 (1H, d,
J=5.05Hz), 3.94-
3.91 (1H, Abq, J=17.9Hz), 3.86 (2H, s), 3.52-3.50 (1H, Abq, J=17.9Hz).
Mass (m/e) 559


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
22
Example 4
Synthesis of (6R,7R)-3-[(4-amino-2-pyrimidinyl)sulfanyl]-8-oxo-7-
[(phenylacety1)-
amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid
1.0 g of benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5- thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was dissolved in dichloromethane
solution and
then cooled to -78°C. 0.336 ml of trifluoromethanesulfonic acid
anhydride and 0.174 ml
of diisopropylethylamine were successively added dropwise to the reaction
solution. The
mixture was stirred for 1.5 hours and then, excessive dichloromethane was
poured. The
to solution was washed with water and saline, dried over magnesium sulfate,
filtered and then
concentrated under reduced pressure. Without further separation, the
subsequent reaction
was conducted.
The resulting triflate and 380 mg of 2-amino-2-pyrimidine thiol were dissolved
in
ml of dimethylformamide and then allowed to initiate the reaction at the
temperature of
15. -20°C. The temperature was slowly increased to room temperature and
then, the reaction
mixture was stirred for 12 hours. The reaction solution was diluted with ethyl
acetate,
washed with saline, dried over anhydrous magnesium sulfate and then filtered.
The
filtrate was distilled under reduced pressure. The residue was treated with
dichloromethane and diethyl ether to precipiate the crystal, which was then
filtered to
20' , obtain benzhydryl (6R,7R)-3-[(4-amino-2-pyrimidinyl)sulfanyl]-8-oxo-7-(
f 2-[(4-pyridi
nyl)sulfanyl]acetyl~amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylate.
The resulting solid was deprotected with 2 ml of trifluoroacetic acid and 0.8
ml of
anisole and then, separated and purified with a high pressure fractional
liquid
chromatography to obtain 30 mg (yield through three steps 3.4%) of the title
compound.
1H-NMR (D20) 8 7.95 (1H, d, J=5.96Hz), 7.40-7.47 (5H, m), 6.40 (1H, d,
J=5.96Hz), 5.94 (1H, d, J=4.58Hz), 5.06 (1H, d, J=4.58Hz), 4.04 (2H, s), 3.79
(2H, Abq,


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
23
J=15. l2Hz).
Mass (m/e) 444
Example 5
, Synthesis of (6R,7R)-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-7-(~2-[(2,6-
dichloro- 4-
pyridinyl)sulfanyl] acetyl) amino)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-
2-
carboxylic acid
2.23 g of benzhydryl 7-amino-3-[(2,6-diamino-4-pyrimidinyl)sulfanyl]-8-oxo- 5-
to thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was treated with
trifluoroacetic acid and
anisole to obtain 1.8 g of deprotected trifluoroacetate compound.
0.20 g (0.4415 mmol) of the resulting (6R,7R)-7-amino-3-[(2,6-diamino-4-
pyrimidinyl)sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid trifluo
roacetate was dissolved in 3 ml of dichloromethane and then cooled to
0°C. 0.44 ml of
1'~T,O-bistrimethylsilyl acetamide was added and the reaction mixture was
stirred at 0°C for
10 minutes. 0.14 g (0.5298 mmol) of 2-[(2,6-dichloro-4-pyridinyl)-
sulfanyl]acetyl ,
chloride and 0.018 ml (0.2208 mmol) of pyridine were added. The temperature of
the
reaction vessel was increased to 10°C and the reaction solution was
stirred for 3 hours.
The reaction was stopped with water and ammonium chloride. The resulting
product was
2o solidified with diethyl ether to obtain 0.10 g of the solid product, which
was then purified
with a high pressure fractional liquid chromatography to obtain 0.038 g (yield
15.4%) of
the title compound.
'H-NMR (D20) 8 7.14 (1H, s), 5.58 (1H, s), 5.40-5.39 (1H, d, J=4.4Hz), 5.01-
4.99
(1H, d, J=4.8Hz), 3.83 (2H, s), 3.58-3.54 (1H, ABq, J=17.6Hz), 3.17-3.13 (1H,
Abq,
J=17.2Hz).


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
24
Mass (m/e) 559
Example 6
Synthesis of (6R,7R)-3-[(2-amino-6-hydroxy-4-pyrimidinyl)sulfanyl]-7-( (2-
[(2,6-
dichloro-4-pyridinyl)sulfanyl]acetyl}amino)-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid
0.20 g (0.4415 mmol) of (6R,7R)-7-amino-3-[(2-amino-6-hydroxy-4-
pyrimidinyl)sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid trifluo
roacetate was dissolved in 3 ml of dichloromethane and then cooled to
0°C. 0.44 ml of
to N,O-bistrimethylsilyl acetamide was added and the reaction mixture was
stirred at 0°C for
minutes. 0.14 g (0.5298 mmol) of 2-[(2,6-dichloro-4-pyridinyl)-sulfanyl]acetyl
chloride and 0.018 ml (0.2208 mmol) of pyridine were added. The temperature of
the
reaction vessel was increased to 10°C and the reaction solution was
stirred for 3 hours.
The reaction was stopped with water and ammonium chloride. The resulting
product was
solidified with diethyl ether to obtain 0.15 g of the solid product, which was
then purified
with a high pressure fractional liquid chromatography to obtain 0.077 g (yield
31.1%) of
the title compound.
'H-NMR (D20) 8 7.02 (2H, s), 5.32-5.30 (1H, d, J=4.4Hz), 5.26 (1H, s), 4.88-
4.87
~ (1,H, d, J=4.8Hz), 3.71-3.68 (2H, q), 3.46-3.42 (1H, ABq, J=17.6Hz), 3.05-
3.01 (1H, Abq,
J=16.8Hz).
Mass (m/e) 560
Experiment 1: Minimum Inhibitory Concentration (MIC)
The effectiveness of the compound according to the present invention was


CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
determined by obtaining Minimum Inhibitory Concentration (MIC) of the
compounds
prepared by the above examples (I-1 to I-6) and vancomycin, which is the known
compound having a potent activity against gram-positive strains, as the
control drug
. against , the standard strains. Specifically, Minimum Inhibitory
Concentration was
5 obtained by diluting the test material with a double dilution method,
dispersing them in
Mueller-Hinton agar medium, inoculating each of the test strain having 10' cfu
(colony
forming unit) per ml in an amount of 2 ,~.e to the medium and then incubating
them at
37°C for 20 hours. The results are shown in the following Tables 1 and
2. From the
result , of Minimum Inhibitory Concentration test, it can be seen that the
compound
10 ' according to the present invention has a good activity against major
pathogenic
microorganisms, which cause hospital infection, including MRSA strains.
Table 1.
Sensitivity test result using standard strains (~Ig/ml)
Staphylococcus.S: au~eusS. auYeusS. E. faecalis
au~eus giorgio77 241 epidermidisL239
8005


I-1 <0.008 0.25 2 0.25 2


I-2 0.031 0.5 4 0.5 2


I-3 0.016 1 4 0.5 2


T-4 4 32 >64 32 >64


Vancomycin1 1 2 1 2




CA 02409329 2002-11-15
WO 02/04463 PCT/KRO1/01026
26
Table 2.
Sensitivity test result using standard strains (~Ig/ml)
StaphylococcusS. au~eusStaphylococcusS. E. faecalis


i ~~ aureus K311 epide~midisEFS004
i


org
aureus g
o


8005


I-5 0.063 1 1 1 4


I-6 0.063 2 1 0.5 2


Vancomycin1 1 2 1 1


While the invention has been described with respect to the above specific
embodiments, it should be recognized that various modifications and changes
can be made
to the invention by those skilled in the art, which also fall within the scope
of the invention
as defined by the appended claims.

Representative Drawing

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Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2001-06-14
(87) PCT Publication Date 2002-01-17
(85) National Entry 2002-11-15
Examination Requested 2002-11-15
Dead Application 2006-06-14

Abandonment History

Abandonment Date Reason Reinstatement Date
2005-06-14 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $400.00 2002-11-15
Registration of a document - section 124 $100.00 2002-11-15
Application Fee $300.00 2002-11-15
Maintenance Fee - Application - New Act 2 2003-06-16 $100.00 2003-05-12
Maintenance Fee - Application - New Act 3 2004-06-14 $100.00 2004-06-08
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
LG LIFE SCIENCES LTD.
Past Owners on Record
JANG, YONG-JIN
KIM, GEUN-TAE
LEE, CHANG-SEOK
LEE, HYANG-SOOK
LEE, SEONG-BAEK
OH, SEONG-HO
RYU, EUN-JUNG
YOUN, HA-SIK
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2002-11-15 1 56
Claims 2002-11-15 5 122
Description 2002-11-15 26 918
Cover Page 2003-02-13 1 29
PCT 2002-11-15 3 114
Assignment 2002-11-15 7 221
PCT 2002-12-16 3 92
PCT 2002-11-15 1 42
PCT 2002-11-16 3 179
Fees 2003-05-12 1 28
Fees 2004-06-08 1 28